Immunoglobulins are composed of the L chains and H chains, each of which consists of a variable region (V region) and a constant region (C region) that has a structure common to immunoglobulin molecules. What determines the antigenic specificity of an antibody is the V region. The V region of the H chain is encoded by V, D (diversity) and J (joining) genes (The gene of the H chain is expressed by placing a suffix “H”, like “VH”). One of the important reasons why the V regions of immunoglobulins are highly diverse and can provide antibodies which specifically binds to infinite number of antigens is the rearrangement of V, D and J genes. That is, there are a plurality of V genes, D genes and J genes, respectively and they are randomly combined in somatic cells to form a gene encoding a single mRNA. Since the combination is randomly selected, wide variety of immunoglobulin V regions are provided.
On the other hand, antibodies currently employed for therapies of various diseases are those originated from animals other than human, such as mouse. However, if these antibodies are administered to human, since the antibodies are of exogenous origin, an immunological response occurs in the human body to present allergy and to neutralize the antibodies. To overcome this problem, it is desired to use antibodies originated from human for the therapies for human. Further, if a human antibody is industrially produced using human as the host and using a human-originated antigen, a problem of immunological tolerance is brought about, so that this approach employing the known method is very difficult. Thus, the production of human immunoglobulins by a genetic engineering process using an animal as a host is now being developed (for example, Japanese Laid-open PCT Application (Kohyo) No. 4-504365; Proc. Natl. Acad. Sci. USA, Vol. 86, pp.5898-5902, August 1989; Proc. Natl. Acad. Sci. USA, Vol. 87, pp.5109-5113, July 1990; Genomics 9, 742-750 (1991)). However, in the conventional methods in which human immunoglobulin genes are expressed in host animals other than human, there is a problem that the number of human VH segments provided for the genetic recombination is very small, so that the diversity of the expressed human immunoglobulins is limited. Even if only one VH segment is recombined, the diversity of the immunoglobulin is assured to some degree because of the combination with D and J genes. However, as mentioned above, since the diversity of immunoglobulins is determined by the rearrangement (random combination) of V gene segments, the more the human VH segments recombined, the higher the diversity of the immunoglobulins expressed. If the diversity of immunoglobulins is increased, not only antibodies against a number of antigens can be formed, but also the possibility of forming an antibody having a high specificity to a given antigen is promoted. Therefore, it in important for therapies and diagnoses to recombine VH segments as many as possible.